The specific aims of this application are to establish the roles of various humoral substances in affecting blood flow distribution, microvascular sites of action and permeability using advanced marocirculatory and microcirculatory methods. Macrocirculatory measurements of blood flow will be made by both the Xe-133 washout and the 15 Mum radioisotope labeled microsphere injection methods in the same intact dog canine tooth. Parallel microcirculatory measurements will be performed on the rat incisor tooth by the intravital microscopy technique; vessel diameter, intravascular red cell velocity and volumetric flow rate will be measured in the pulpal microvasculature. In addition, microvascular permeability will be investigated with fluorescent-labeled macromolecules. Using these methods, the effects of various humoral interventions on macrocirculatory and microcirculatory dynamics of the pulp will be investigated. Following subclassification of Alpha-adrenergic receptors in the pulpal vessels, interaction between the Alpha-adrenergic receptors and humoral substances will also be determined by simultaneous application of both stimuli. The possible modulating effects of prostaglandins (PBs) on various humoral substances (bradykinin, histamine, substance P and 5-Hydroxytryptamine) and on sympathetic activity on pulpal hemodynamics will be examined by injecting arachidonic acid, a PG synthesis precursor, preceding the stimuli. The PG synthesis blocker indomethacin will also be used to determine its blocking effect. The effects of antidromic stimulation of the inferior alveolar nerve, which releases a substance P-like substance, and the effects of intraarterial administration of substance P will be compared and analyzed to establish their roles in the local regulation of pulp circulation and in the neurovascular activity of the pulp. These studies, by using advanced macrocirculatory and newly developed microcirculatory techniques, promise to attain the long term objective of elucidating the humoral mechanisms in the regulation of pulpal hemodynamics and to add a body of knowledge to understanding the pathophysiological mechanisms of pulpal disorders.